Fosamprenavir calcium has HIV aspartyl protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses; it is chemically known as calcium (3S)tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl carbamate and represented by formula Ia.

There are very few references available in the literature for preparation of fosamprenavir and its intermediates. U.S. Pat. No. 5,585,397 provides process for preparation of fosamprenavir intermediate (IV), as depicted in scheme 1, wherein it is purified using silica gel chromatography, however it does not provide any purity data. Purification by column chromatography is not suitable on commercial scale, since it is time consuming, requires large volume of solvents and is very much laborious.

Another U.S. Pat. No. 6,281,367, provides process for preparation of fosamprenavir intermediate (IV) as depicted in scheme 2, but it does not provide any method for purification of compound (IV).

The U.S. Pat. No. 6,514,953 provides process for preparation of fosamprenvair calcium (Ia) utilizing compound (IV), as depicted in Scheme 3, however it does not provide purity of fosamprenavir calcium (Ia) or the intermediates thereof.

Another U.S. Pat. No. 6,436,989, which is product patent for fosamprenavir salts, provide process for preparation of fosamprenavir sodium salt (VII) from compound (IV) as depicted in Scheme 4:

U.S. Pat. No. 6,436,989 provides compound (V) and (VIA) with an HPLC purity of 90% and 92% respectively, however purity of fosamprenavir sodium salt (VII) is not mentioned. This patent provides fosmaprenavir salt intermediates with very low HPLC purity.
The prior art literature describes synthesis of fosamprenavir calcium and its intermediates and like any synthetic compound, fosmaprenavir calcium can contain number of impurities from various source like starting material, reaction by-products, degradation, isomeric impurities etc. The prior art documents for fosamprenavir calcium does not provide any information for the impurities that may have been formed from the various synthetic processes provided therein.
Fosamprenavir calcium i.e. calcium (3S)tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl carbamate (Ia), is a chiral substrate containing three asymmetrical carbon centre resulting into eight stereoisomers.
Different isomers of a chiral drug molecule bind differently to target receptors, one isomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects or sometimes even beneficial but entirely different effects, hence in the drug molecules the effective isomer is preferred in pure form, free of other undesired isomers, thus fosamprenavir calcium free of its other stereoisomer would always be preferred.
The methods described above for preparation of fosamprenavir does not describe suitable methods to minimize formation of R-isomer impurity (Ib)

One of the approach to minimize R-isomer impurity (Ib) is to use highly pure intermediate (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (IIa), in the synthesis of fosamprenavir.
U.S. Pat. No. 5,585,397 provides process for preparation of N-succinimidlyl-(S)-3-tetrahydrofuryl carbonate (IIa), however it does not provide any method for purification neither does it provide any purity data for the same.
The PCT application WO 94/18192 provides process for preparation (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (IIa) as depicted in scheme 5. The application discloses recrystallization of compound (IIa) from EtOAc/hexane. At our hands, crystallization of compound (IIa) from ethyl acetate/hexane provided compound (IIa) containing the intermediate R-isomer impurity compound (IIb) upto 0.37% area percentage of HPLC, which is not suitable for its use in the synthesis of fosamprenavir substantially free of R-isomer impurity (Ib).

Commercially available (S)-3-tetrahydrofuranol (VIIIa) contains upto 5% area percentage of HPLC of (R)-3-tetrahydrofuranyl (VIIIb), which on reaction with N,N-disuccinimidyl carbonate (IX) results in (S)-3-tetrahydro furanyl-N-succinimidyl carbonate (IIa) containing upto 2.5% area percentage of HPLC of the R-isomer impurity, (R)-3-tetrahydrofuranyl-N-succinimidyl carbonate (IIb). This impure (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (IIa) when converted to fosamprenavir calcium (Ia) by series of reaction, results into fosamprenavir calcium containing upto 2.0% area percentage of HPLC of (3R)tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl carbamate (Ib), which is undesired isomer of fosamprenavir calcium.
Impurities of any form are undesirable in the active pharmaceutical product since it may have adverse effect on the patient to be treated.
The purity of API produced is clearly a necessary condition for commercialization. The impurities produced in the manufacturing process must be limited to very small amount and are preferred to be substantially absent. The ICH Q7A guidance for API manufacturers requires that process impurities must be maintained below set limits utilizing various parameters. In the United States the Food and Drug Administration guidelines, would mostly limit the amount of impurities present in the API, similarly in other countries the impurity levels would be defined in their respective pharmacopeias.
Fosamprenavir calcium is not a pharmacopeial product at present and the guidelines for the amount of impurities is not provided, however substantially pure fosamprenavir calcium would always be preferred. The objective to the present invention is directed to the same.